Eur J Clin Invest 2010 ABSTRACT: Background The metabolic syndrome is associated with coronary artery disease (CAD) and with peripheral artery disease (PAD), but the underlying mechanisms explaining these associations have not yet been completely clarified. The aim was to investigate (i) whether endothelial dysfunction can explain the association between the metabolic syndrome and CAD and/or the severity of PAD, as measured by the ankle-arm index (AAIx); and (ii) whether any such mediation is independent of that from low-grade inflammation. Materials and methods We studied 539 subjects (232 men) aged 59.4 +/- 6.9 years, with an increased risk of type 2 diabetes and cardiovascular diseases. Endothelial dysfunction and inflammation scores were calculated from three markers of endothelial dysfunction (soluble E-selectin, soluble vascular cell adhesion molecule-1 and von Willebrand factor) and six of inflammation (C-reactive protein, interleukin 6, soluble intercellular adhesion molecule-1, serum amyloid A, ceruloplasmin and haptoglobin). The association between the metabolic syndrome and CAD and/or PAD, and the mediating role of endothelial dysfunction herein was examined with logistic and linear regression analyses, all adjusted for age, sex and smoking. Results Subjects with the metabolic syndrome (n = 289; 54%) had higher prevalence of CAD [OR (95%CI) = 1.75 (1.14; 2.69)] and lower AAIx [beta (95% CI) = -0.036 (-0.056; -0.016)]. Endothelial dysfunction explained 6% of the association between the metabolic syndrome and CAD, and 19% of the association with AAIx, whereas low-grade inflammation explained 26% and 28% of these associations, respectively. Together, the two scores explained 24% and 36% of the association between the metabolic syndrome and CAD and AAIx, respectively. Conclusions Endothelial dysfunction explains part of the association between the metabolic syndrome and the severity of PAD, but is not involved in the association between the metabolic syndrome and CAD. This indicates that the pathophysiologies of coronary and peripheral artery disease are essentially distinct.